CN110172038A - The technique that one kettle way prepares analgin magnesium - Google Patents
The technique that one kettle way prepares analgin magnesium Download PDFInfo
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
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Abstract
The invention discloses the techniques that one kettle way prepares analgin magnesium, and the method is using 4- novalgin, formaldehyde and magnesium salts or its oxide as raw material, with SO21- phenyl -2 is made in gas reaction, 3- dimethyl -4- methylamino pyrazolin-5-one-N- methane sulfonic acid magnesium crude product, 1- phenyl -2,3- dimethyl -4- methylamino pyrazolin-5-one-N- methane sulfonic acid magnesium hexahydrate is made by recrystallization further purification in above-mentioned crude product again.Present invention process step is simple, and raw material is cheap and easy to get, and the analgin magnesium product yield of synthesis is high, high-quality and process stabilizing, is suitable for industrial production.
Description
Technical field
The present invention relates to field of medicaments, and specifically, the present invention relates to a kind of 1- phenyl -2,3- dimethyl -4- methylaminos
The hexahydrated preparation method of pyrazolin-5-one-N- methane sulfonic acid magnesium and refining methd.
Background technique
Analgin magnesium (1- phenyl -2,3- dimethyl -4- methylamino pyrazolin-5-one-N- methane sulfonic acid magnesium hexahydrate),
Promptly bringing down a fever when can be used for acute high fever, also can be used for having a headache, migraine, courbature, rheumatic neuralgia, toothache, joint
Pain and cramp etc.；It can also make veterinary drug for courbature, rheumatism, heat generation illness and colic etc., skeleton symbol is as follows:
Pass through comprehensive literature survey, it has been found that preparing the method for analgin magnesium, there are mainly two types of:
Method one: patent CN99120402.6 is reported analgin and magnesium chloride, magnesium sulfate in methanol, ethyl alcohol or isopropyl
Analgin magnesium is synthesized by the method that metal ion is replaced in alcohol.The main problem of this method is sodium ion and magnesium ion at this
Under the conditions of property it is closely similar, be difficult to replace completely；Magnesium sulfate is almost insoluble in methanol, ethyl alcohol or isopropanol, cause sodium from
Son and magnesium ion not can be carried out effective displacement, thus the conversion effect of analgin magnesium is poor, yield is low, quality is bad.
Method two: Zikolov, P is in document (Farmatsiya (Sofia, Bulgana), 1976,20 (6), 11~17)
It reports and analgin is removed into sodium ion by cation exchange resin, then exchanged with magnesium ion, tied finally by concentration
Brilliant method prepares analgin magnesium.The main problem of this method is that ion exchange resin is expensive, and analgin magnesium is water-soluble
It is also unstable in liquid, cause unstable product quality and production cost higher.
In view of the above-mentioned problems, the present invention is directed to design a kind of one kettle way process, raw material is cheap and easy to get, overall yield of reaction is high and
The preparation process of the high analgin magnesium of product quality, to overcome the deficiencies of existing technologies and shortcoming.
Summary of the invention
According to the one aspect of the application, providing a kind of technique that one kettle way prepares analgin magnesium (can also hereafter become
Preparation method).
Specifically, one kettle way provided by the present invention prepares the technique of analgin magnesium, with 4- novalgin (under
Text is alternatively referred to as MAA), formaldehyde and magnesium salts be raw material, with SO2Gas reaction is made.
Some specific embodiments according to the present invention, the magnesium salts or its oxide are selected from magnesia, magnesium carbonate, alkali formula carbon
One of sour magnesium and magnesium hydroxide or a variety of combinations, preferably magnesia.
Some specific embodiments according to the present invention, above-mentioned reaction process (preparing crude product) carry out in reaction medium, institute
It states reaction medium and is selected from one of methanol, ethyl alcohol and isopropanol or a variety of combinations；It is preferred that isopropanol.
Some specific embodiments according to the present invention, Xiang Suoshu raw material formed system in be passed directly into SO2Gas carries out
The reaction of one cooking-pot type；It is preferred that first 4- novalgin, formaldehyde and magnesium salts are dispersed in reaction medium, then into dispersion
It is passed through SO2Gas, venting pressure were controlled in 5~150psi (preferably ventilatory capacity makes reaction pressure be advisable in 10-100psi).?
Under above-mentioned venting pressure, draft speed and ventilatory capacity can control, have the advantages that control reaction carry out degree.
Some specific embodiments according to the present invention, Xiang Suoshu raw material formed system in be passed directly into SO2Gas uses
Air-blowing method or sulks method.
Some specific embodiments according to the present invention, wherein MAA and magnesium salts or its oxide (preferably magnesia) rub
You are than being (0.8~1.2): 1；
And/or:
The mass ratio of reaction medium and MAA are (1-20): 1, preferably 4:1.
Technique of the present invention, formaldehyde can be provided in the form of its solution or solid formaldehyde, be used as polymerizer, be added
To after reaction system, MAA, SO can be made2, magnesia be combined into analgin magnesium；Its dosage is with magnesia: MAA is advisable for 1~1.4.
Some specific embodiments according to the present invention terminate reaction when the pH value of reaction system of the reaction is 3~5.
Some specific embodiments according to the present invention, wherein judge that reaction end can take ventilation late detection reactant
It is that method (MAA≤0.5%) of the pH value in 3~5 and/or reaction solution sampling inspection HPLC is used as standard.
Some specific embodiments according to the present invention, wherein reaction temperature is 0~80 DEG C.
As a preferred solution of the present invention, the technique further includes by the 1- phenyl -2,3- obtained after reaction
Dimethyl -4- methylamino pyrazolin-5-one-N- methane sulfonic acid magnesium crude product (can also hereafter become analgin magnesium crude product or ANJ-Mg
Crude product) the step of being recrystallized；
It is preferred that the recrystallization are as follows: first to the 1- phenyl -2,3- dimethyl -4- methylamino pyrazolin-5-one-N- first
The reaction medium aqueous solution is added in base sulfonic acid magnesium crude product, active carbon, heating thermosol filtering are added afterwards, then filtrate is analysed
It is brilliant.
Some specific embodiments according to the present invention, wherein activated carbon dosage is the 0.2%- of analgin magnesium crude product dosage
10%.
Some specific embodiments according to the present invention, wherein reaction medium aqueous solution used in recrystallization process is
One of methanol, ethyl alcohol, isopropanol, butanol, acetone and butanone or a variety of mixtures have with through boil that purified water matches
Solvent aqueous solution；It is preferred that isopropanol water solution, the more preferably mass ratio of the two are (1-20): 1, select isopropanol water solution to make
Help to recrystallize more abundant, raising reaction yield for reaction medium aqueous solution.
Preferably, in technique of the present invention, previous reaction medium and recrystallization are using " anti-in reaction medium aqueous solution
Answer medium " selection is unanimously.
Some specific embodiments according to the present invention, wherein be stirred heating after active carbon is added, system reflux is protected
Temperature, temperature are 60~85 DEG C.
Some specific embodiments according to the present invention, wherein crystallization temperature is 0-25 DEG C.
Some specific embodiments according to the present invention, wherein organic solvent used in preparation ANJ-Mg crude product is selected from first
One of alcohol, ethyl alcohol, isopropanol, butanol, acetone and butanone or a variety of mixing.
Some specific embodiments according to the present invention, wherein the step of purification (can also be expressed as purification step)
Include: that active carbon is added into the mixed solution of analgin magnesium crude product and reaction medium aqueous solution, flows back at 60~85 DEG C de-
Color is simultaneously filtered, cooling crystallization (being preferably cooled to 0~5 DEG C of heat preservation again) while hot, obtains the analgin magnesium finished product of high-quality.
Some specific embodiments according to the present invention, wherein purification filter cake can take vacuum drying, forced air drying and whirlwind
It is dry.
The technique that the present invention prepares analgin magnesium salts is: the first step is to prepare analgin magnesium crude product, and method is by MAA, magnesium
Salt or its oxide, formaldehyde reaction medium (preferably isopropanol) dispersion in be passed through SO2It is reacted, by filtering, doing
It is dry to obtain analgin magnesium crude product；Second step is to prepare analgin magnesium finished product, and method is: reaction medium water is added in the crude product of drying
Active carbon is added in solution (preferably isopropanol water solution), carries out heat of solution, filters after heat preservation, and filtrate is recrystallized, and filters and dries
It is dry to obtain finished product.
Specifically:
Step 1: 4- novalgin (MAA), magnesium salts or its oxide, formalin (or paraformaldehyde) are pressed
Ratio is scattered in reaction medium, is passed through SO2Gas is reacted, and is determined reaction end by surveying late phase reaction pH value, must be pacified
It is nearly magnesium crude product；
The reaction medium is selected from methanol, ethyl alcohol, isopropanol, butanol, acetone, butanone or their any combination, excellent
Select isopropanol；
The magnesium salts or its oxide are selected from magnesia, magnesium carbonate, basic magnesium carbonate or magnesium hydroxide, preferably aoxidize
Magnesium；
The weight ratio of MAA and reaction medium is 1:1~20；The molar ratio of MAA and formalin is 1:1.0~2.0；Reaction
Temperature is 0~80 DEG C, and preferably 40 DEG C, reaction pressure is 10~100psi, preferably 30psi；
Step 2: dispersing analgin crude product in reaction medium aqueous solution, active carbon is added, it is de- that heating carries out dissolution
Color.Filter while hot, mother liquor crystallization (preferably stirring (120~360r/min) under Temperature fall), filter, dry analgin magnesium at
Product；
The reaction medium aqueous solution preferably uses isopropanol water solution, wherein isopropanol is 1:(0.1 with water molar ratio
~4)；The quality additional amount of active carbon is 0.2%-10%；60~85 DEG C of heating temperature, preferably 82 DEG C.
The beneficial effect that the application can generate includes:
Present invention process is simple, high income, detection purity is high and the process stabilizing of the analgin magnesium prepared.
Detailed description of the invention
Fig. 1 is analgin magnesium finished product UV map；
Fig. 2 is analgin magnesium finished product HPLC-UV detection；
Fig. 3 is analgin magnesium finished product infrared detection map.
Specific embodiment
The application is described in detail below with reference to embodiment, but the application is not limited to these embodiments.
Unless otherwise instructed, the raw material in embodiments herein and catalyst are bought by commercial sources.
One, prepared by ANJ-Mg crude product
Embodiment 1
By compound 4- novalgin (MAA) (217.3g, 1mol), MgO (40.3g, 1mol) formalin
(110g, mass fraction 36%) and 550ml methanol are added in 1L reaction flask, and stirring makes system scatter at 20~30 DEG C, are delayed
Slowly it is passed through SO2Gas, reaction temperature are 30~80 DEG C, and the later period of ventilating judges reaction end with PH test paper.And at 20~50 DEG C
Insulated and stirred 1h.Reaction system is cooled to 0~25 DEG C, is filtered after keeping the temperature crystallization 2h, rinses filter cake, drum with a small amount of ice isopropanol
It air-dries dry rear up to analgin magnesium (ANJ-Mg) 350.2g, yield 93%.
Embodiment 2
By compound MMA (217.3g, 1mol), MgO (40.3g, 1mol), formalin (110g, mass fraction 36%)
It is added in 1L reaction flask with 550ml isopropanol, and leads to sulfur dioxide into reaction flask, reaction temperature is 30~80 DEG C, HPLC
Purity≤0.5% of MAA determines that reaction terminates in monitoring reaction system.Reaction solution ice-water bath is cooled to 0~5 DEG C and is kept the temperature
Crystallization 2h is filtered, and filter cake is eluted with a small amount of ice isopropanol, up to analgin magnesium 354.0g, yield 94% after forced air drying.
Embodiment 3
By compound MMA (217.3g, 1mol), MgO (40.3g, 1mol), formalin (110g, mass fraction 36%)
Be added in 1L reaction flask with 550ml ethyl alcohol, sulfur dioxide be passed through into reaction flask, be pressurized to reaction flask internal pressure be 40~
60psi is heated to 40~80 DEG C of reactions.If reacting bottle pressure decline, continues logical sulfur dioxide, maintain reaction flask internal pressure
For 20~50psi.To reaction flask internal pressure, pressure is basically unchanged in 0.5~1 hour for reaction, is down to room temperature, reaction solution ice
Water-bath is cooled to 0~5 DEG C and keeps the temperature crystallization 2h, filters, with a small amount of ice ethanol rinse filter cake, up to analgin magnesium after forced air drying
338.9g yield 90%.
Table 1: the influence of solvent type and dosage to analgin magnesium crude yield is prepared
Embodiment 4
By compound 4- novalgin (MAA) (217.3g, 1mol), MgO (40.3g, 1mol) formalin
(110g, mass fraction 36%) and 550ml methanol are added in 1L reaction flask, and stirring makes system scatter at 20~30 DEG C, are delayed
Slowly it is passed through SO2Gas, reaction temperature are 30~80 DEG C, and the later period of ventilating judges reaction end with PH test paper.And at 20~50 DEG C
Insulated and stirred 1h.Reaction system is cooled to 0~25 DEG C, is filtered after keeping the temperature crystallization 2h, rinses filter cake, drum with a small amount of ice isopropanol
It air-dries dry rear up to analgin magnesium (ANJ-Mg) 302g, yield 80.2%.
Embodiment 5
By compound 4- novalgin (MAA) (217.3g, 1mol), Mg (OH)2(58.3g, 1mol) formaldehyde is molten
Liquid (110g, mass fraction 36%) and 550ml isopropanol are added in 1L reaction flask, and stirring disperses system at 20~30 DEG C
It opens, is slowly introducing SO2Gas, reaction temperature are 30~80 DEG C, and the later period of ventilating judges reaction end with PH test paper.And in 20~50
Insulated and stirred 1h at DEG C.Reaction system is cooled to 0~25 DEG C, is filtered after keeping the temperature crystallization 2h, is rinsed and is filtered with a small amount of ice isopropanol
Cake, up to analgin magnesium (ANJ-Mg) 320.1g g, yield 85% after forced air drying.
Embodiment 6
By compound 4- novalgin (MAA) (217.3g, 1mol), MgCO3(84g, 1mol) formalin
(110g, mass fraction 36%) and 550ml ethyl alcohol are added in 1L reaction flask, and stirring makes system scatter at 20~30 DEG C, are delayed
Slowly it is passed through SO2Gas, reaction temperature are 30~80 DEG C, and the later period of ventilating judges reaction end with PH test paper.And at 20~50 DEG C
Insulated and stirred 1h.Reaction system is cooled to 0~25 DEG C, is filtered after keeping the temperature crystallization 2h, rinses filter cake, drum with a small amount of ice isopropanol
It air-dries dry rear up to analgin magnesium (ANJ-Mg) 328.4g g, yield 87.2%.
Embodiment 7
By compound 4- novalgin (MAA) (217.3g, 1mol), 4MgCO3·Mg(OH)2·5H2O
(97.2g, 0.2mol) formalin (110g, mass fraction 36%) and 550ml isopropanol are added in 1L reaction flask, and 20~30
Stirring makes system scatter at DEG C, is slowly introducing SO2Gas, reaction temperature are 30~80 DEG C, and the ventilation later period is judged with PH test paper
Reaction end.And the insulated and stirred 1h at 20~50 DEG C.Reaction system is cooled to 0~25 DEG C, is filtered after keeping the temperature crystallization 2h, is used
A small amount of ice isopropanol rinses filter cake, up to analgin magnesium (ANJ-Mg) 328.4g g, yield 87.2% after forced air drying.
Table 2: the influence of magnesium salts type and solvent type to analgin magnesium yield
Embodiment 8
By compound MAA (217.3g, 1mol), MgCO3(84g, 1mol) formalin (110g, mass fraction 36%) and
550ml ethyl alcohol is added in 1L reaction flask, and sulfur dioxide is led in reaction flask, and reaction temperature is 60~85 DEG C, HPLC monitoring reaction
Purity≤0.5% of MAA determines that reaction terminates in system.And the insulated and stirred 1h at 20~50 DEG C.Reaction system is cooled down
It to 0~25 DEG C, is filtered after keeping the temperature crystallization 2h, filter cake is rinsed with a small amount of ice ethyl alcohol, up to analgin magnesium crude product after forced air drying
(ANJ-Mg) 328.4g g, yield 87.2%.
Embodiment 9
By compound 4- novalgin (MAA) (217.3g, 1mol), MgCO3(84g, 1mol) formalin
(110g, mass fraction 36%) and 550ml ethyl alcohol are added in 1L reaction flask, and sulfur dioxide is passed through into reaction flask, is pressurized to
Reaction flask internal pressure is 20~50psi, is heated to 60~80 DEG C of reactions.If reacting bottle pressure decline, continue logical titanium dioxide
Sulphur, maintenance reaction flask internal pressure are 20~50psi.To reaction flask internal pressure, pressure is not substantially in 0.5~1 hour for reaction
Become, be down to room temperature, reaction solution ice-water bath is cooled to 0~5 DEG C and keeps the temperature crystallization 2h, filters, with a small amount of ice ethanol rinse filter cake, drum
It air-dries dry rear up to analgin magnesium crude product 338.9g, yield 90%.
Embodiment 10
By compound 4- novalgin (MAA) (217.3g, 1mol), MgO (40.3g, 1mol) formalin
(110g, mass fraction 36%) and 550ml methanol are added in 1L reaction flask, and sulfur dioxide is passed through into reaction flask, is pressurized to
Reaction flask internal pressure is 20~50psi, is heated to 60~80 DEG C of reactions.If reacting bottle pressure decline, continue logical titanium dioxide
Sulphur, maintenance reaction flask internal pressure are 20~50psi.To reaction flask internal pressure, pressure is not substantially in 0.5~1 hour for reaction
Become, room temperature is down in stirring, and ice-water bath is cooled to 0~5 DEG C and keeps the temperature crystallization 2h, is filtered, and elutes filter cake, vacuum with a small amount of ice methanol
Up to analgin magnesium crude product 331.4g, yield 88% after drying.
Embodiment 11
By compound 4- novalgin (MAA) (217.3g, 1mol), MgO (40.3g, 1mol) formalin
(110g, mass fraction 36%) and 550ml ethyl alcohol are added in 1L reaction flask, and sulfur dioxide is led in reaction flask, and reaction temperature is
65~75 DEG C, purity≤0.5% that HPLC monitors MAA in reaction system determines that reaction terminates.Room temperature, ice-water bath are down in stirring
It is cooled to 0~5 DEG C and keeps the temperature crystallization 2h, filter, with a small amount of ice ethanol rinse filter cake, up to analgin magnesium crude product after vacuum drying
330.6g yield 87.8%.
Embodiment 12
By compound 4- novalgin (MAA) (217.3g, 1mol), MgO (40.3g, 1mol) formalin
(110g, mass fraction 36%) and 550ml ethyl alcohol are added in 1L reaction flask, and sulfur dioxide is passed through into reaction flask, is pressurized to
Reaction flask internal pressure is 20~50psi, is heated to 60~80 DEG C of reactions.If reacting bottle pressure decline, continue logical titanium dioxide
Sulphur, maintenance reaction flask internal pressure are 20~50psi.To reaction flask internal pressure, pressure is not substantially in 0.5~1 hour for reaction
Become, room temperature is down in stirring, and ice-water bath is cooled to 0~5 DEG C and keeps the temperature crystallization 2h, is filtered, with a small amount of ice ethanol rinse filter cake, vacuum
Up to analgin magnesium crude product 351.7g after drying, yield 93.4%, HPLC purity is 99.58%.
Embodiment 13
By compound 4- novalgin (MAA) (217.3g, 1mol), MgO (40.3g, 1mol) formalin
(110g, mass fraction 36%) and 550ml ethyl alcohol are added in 1L reaction flask, and sulfur dioxide is passed through into reaction flask, is pressurized to
Reaction flask internal pressure is 20~50psi, is heated to 60~80 DEG C of reactions.If reacting bottle pressure decline, continue logical titanium dioxide
Sulphur, maintenance reaction flask internal pressure are 20~50psi.To reaction flask internal pressure, pressure is not substantially in 0.5~1 hour for reaction
Become, room temperature is down in stirring, and ice-water bath is cooled to 0~5 DEG C and keeps the temperature crystallization 2h, is filtered, with a small amount of ice ethanol rinse filter cake, vacuum
Up to analgin magnesium crude product 388.9g, yield 90.0% after drying.
Embodiment 14
By compound 4- novalgin (MAA) (217.3g, 1mol), MgO (40.3g, 1mol) formalin
(110g, mass fraction 36%) and 550ml butanol are added in 1L reaction flask, and sulfur dioxide is passed through into reaction flask, is pressurized to
Reaction flask internal pressure is 20~50psi, is heated to 60~80 DEG C of reactions.If reacting bottle pressure decline, continue logical titanium dioxide
Sulphur, maintenance reaction flask internal pressure are 20~50psi.To reaction flask internal pressure, pressure is not substantially in 0.5~1 hour for reaction
Become, room temperature is down in stirring, and ice-water bath is cooled to 0~5 DEG C and keeps the temperature crystallization 2h, is filtered, and elutes filter cake, vacuum with a small amount of ice butanol
Up to analgin acid 316.3g, yield 84.0% after drying.
Table 3: the influence of solvent type and reaction pressure to analgin magnesium crude yield
Two, crude product recrystallizes
Embodiment 15
Reaction flask is added in analgin magnesium crude product (217.3g, embodiment 1 are made) and 500ml methanol aqueous solution (10:1),
Active carbon is added, is stirred heating, makes system reflux heat preservation, control temperature of reaction system is 60-85 DEG C, insulation reaction
0.5h.It filters while hot, filtrate is placed in stirring and crystallizing in 50-60 DEG C of water-bath, make its Temperature fall, when system is down to room temperature,
Reaction flask is placed in 0-5 DEG C of water-bath and keeps the temperature 2h；It filters, filter cake is placed in air dry oven and dries, and obtains analgin magnesium finished product
265.5g, yield 70.5%, HPLC purity are that 99.90%, UV map, HPLC-UV detection and infrared detection map are shown in respectively
Fig. 1-Fig. 3.
Embodiment 16
Reaction flask is added in analgin magnesium crude product (217.3g, embodiment 2 are made) and 500ml ethanol water (4:1), is added
Enter active carbon, be stirred heating, be system reflux heat preservation, control temperature of reaction system is 60-85 DEG C, insulation reaction 0.5h.
It filters while hot, filtrate is placed in stirring and crystallizing in 50-60 DEG C of water-bath, makes its Temperature fall, when system is down to room temperature, will react
Bottle, which is placed in 0-5 DEG C of water-bath, keeps the temperature 2h；It filtering, filter cake is placed in air dry oven and dries, analgin magnesium finished product 152.5g is obtained,
Yield is that 40.5%, HPLC purity is 99.88%.
Embodiment 17
Reaction flask is added in analgin magnesium crude product (217.3g, embodiment 3 are made) and 500ml isopropanol water solution (6:1),
Active carbon is added, is stirred heating, is system reflux heat preservation, control temperature of reaction system is 60-85 DEG C, insulation reaction
0.5h.It filters while hot, filtrate is placed in stirring and crystallizing in 50-60 DEG C of water-bath, make its Temperature fall, when system is down to room temperature,
Reaction flask is placed in 0-5 DEG C of water-bath and keeps the temperature 2h；It filters, filter cake is placed in air dry oven and dries, and obtains analgin magnesium finished product
282.4g, yield 75.0%, HPLC purity are 99.92%.
Table 4: the influence of magnesium salts type and solvent type to analgin magnesium yield and quality
Present invention process is simple, high income, quality height and the process stabilizing of the analgin magnesium prepared, embodiment 15-17
Product testing parameter meets following testing result, and (UV map, HPLC-UV detection and infrared detection map are shown in Fig. 1-figure respectively
3):
The above is only several embodiments of the application, not does any type of limitation to the application, although this Shen
Please disclosed as above with preferred embodiment, however not to limit the application, any person skilled in the art is not taking off
In the range of technical scheme, a little variation or modification are made using the technology contents of the disclosure above and is equal to
Case study on implementation is imitated, is belonged in technical proposal scope.
Claims (10)
1. the technique that one kettle way prepares analgin magnesium, which is characterized in that with 4- novalgin, formaldehyde and magnesium salts or its oxygen
Compound is raw material, with SO2Gas reaction is made.
2. technique according to claim 1, which is characterized in that the magnesium salts or its oxide be selected from magnesia, magnesium carbonate,
One of basic magnesium carbonate and magnesium hydroxide or a variety of combinations, preferably magnesia.
3. technique according to claim 1 or 2, which is characterized in that the reaction carries out in reaction medium, the reaction
Medium is selected from one of methanol, ethyl alcohol and isopropanol or a variety of combinations；It is preferred that isopropanol.
4. technique according to claim 1-3, which is characterized in that directly logical in the system that Xiang Suoshu raw material is formed
Enter SO2Gas carries out a cooking-pot type reaction；
It is preferred that first 4- novalgin, formaldehyde and magnesium salts are dispersed in reaction medium, then SO is passed through into dispersion2
Gas, venting pressure are controlled in 5~150psi.
5. technique according to claim 4, which is characterized in that the amount ratio of the 4- novalgin and magnesium salts is
(0.8~1.2): 1；
And/or the mass ratio of the 4- novalgin and the reaction medium is 1:(1-20).
6. technique according to claim 1-5, which is characterized in that when the pH value of reaction system of the reaction is 3
Reaction is terminated when~5.
7. technique according to claim 1-6, which is characterized in that the technique further includes terminating the reaction
The step that the 1- phenyl -2,3- dimethyl -4- methylamino pyrazolin-5-one-N- methane sulfonic acid magnesium crude product obtained afterwards is recrystallized
Suddenly；
It is preferred that the recrystallization are as follows: first to the 1- phenyl -2,3- dimethyl -4- methylamino pyrazolin-5-one-N- methyl sulphur
Reaction medium aqueous solution is added in sour magnesium crude product, active carbon, heating thermosol filtering are added afterwards, then filtrate is recrystallized.
8. technique according to claim 7, which is characterized in that the reaction medium aqueous solution by reaction medium with through over-cooking
The purified water of boiling deoxygenation is formulated.
9. technique according to claim 7 or 8, which is characterized in that using filtering while hot, filtrate uses gradient for the filtering
Cool down stirring and crystallizing, is cooled to room temperature since 50 DEG C, and the temperature of control system is 0~5 DEG C, stirring heat preservation 2 hours.
10. according to the described in any item techniques of claim 7-9, which is characterized in that the re-crystallization step includes: by the 1-
Phenyl -2,3- dimethyl -4- methylamino pyrazolin-5-one-N- methane sulfonic acid magnesium crude product and the reaction medium aqueous solution are returning
Dissolved clarification, active carbon decoloring, filtering, filtrate cooling and stirring crystallization under the conditions of stream, then it is cooled to 0~5 DEG C of heat preservation, weight is obtained after suction filtration
1- phenyl -2,3- dimethyl -4- methylamino pyrazolin-5-one-N- methane sulfonic acid magnesium the hexahydrate of crystallization.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU991716A1 (en) * | 1981-05-06 | 1987-12-30 | Институт физико-органической химии и углехимии АН УССР | 8-(n-methoxyphenyl)-1,3-dimethylimidazo-4/4',5'-c/-imidazo /1,2-a/ pyridine-2-on possessing analgetic and antiinflammatory activity |
| CN1297889A (en) * | 1999-12-01 | 2001-06-06 | 山东新华制药股份有限公司 | Preparation of magnesium [(1,5-dimethyl-2-phenyl-3-oxy-2,3-dioxy-1H-pyrazol-4-yl)methylamino] methane sulfonate hexahydrate |
| CN102399191A (en) * | 2011-12-21 | 2012-04-04 | 武汉武药制药有限公司 | Method for synthesizing analgin |
| CN102627608A (en) * | 2012-03-31 | 2012-08-08 | 武汉武药制药有限公司 | Preparation method for analgesic and antipyretic drug-analgin |
| CN102659680A (en) * | 2012-03-31 | 2012-09-12 | 武汉武药制药有限公司 | Method for palladium-carbon catalytic hydrogenation synthesis of analgin |
| CN106279031A (en) * | 2016-08-08 | 2017-01-04 | 河北冀衡（集团）药业有限公司 | The method that the MAA crystallization using water soluble method to obtain produces COS dipyrone |
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2018
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| Publication number | Priority date | Publication date | Assignee | Title |
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| SU991716A1 (en) * | 1981-05-06 | 1987-12-30 | Институт физико-органической химии и углехимии АН УССР | 8-(n-methoxyphenyl)-1,3-dimethylimidazo-4/4',5'-c/-imidazo /1,2-a/ pyridine-2-on possessing analgetic and antiinflammatory activity |
| CN1297889A (en) * | 1999-12-01 | 2001-06-06 | 山东新华制药股份有限公司 | Preparation of magnesium [(1,5-dimethyl-2-phenyl-3-oxy-2,3-dioxy-1H-pyrazol-4-yl)methylamino] methane sulfonate hexahydrate |
| CN102399191A (en) * | 2011-12-21 | 2012-04-04 | 武汉武药制药有限公司 | Method for synthesizing analgin |
| CN102627608A (en) * | 2012-03-31 | 2012-08-08 | 武汉武药制药有限公司 | Preparation method for analgesic and antipyretic drug-analgin |
| CN102659680A (en) * | 2012-03-31 | 2012-09-12 | 武汉武药制药有限公司 | Method for palladium-carbon catalytic hydrogenation synthesis of analgin |
| CN106279031A (en) * | 2016-08-08 | 2017-01-04 | 河北冀衡（集团）药业有限公司 | The method that the MAA crystallization using water soluble method to obtain produces COS dipyrone |
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